Higher Expression Levels of the Adhesion Molecules VLA-4 and ICAM-1 on Multiple Myeloma Cells after Chemotherapy Are Associated with Survival of a Multidrug Resistant Subpopulation in Vivo.

Objectives: Primary drug resistance is a major problem in multiple myeloma (MM), an incurable disease of the bone marrow. Adhesion of multiple myeloma cells to bone marrow stromal cells (BMSC) has been shown to cause strong primary resistance. The adhesion molecules LFA-1 and VLA-4 are upregulated upon treatment with cytotoxic agents. Furthermore, we have shown that the corresponding ligands on HS-5 BMSCs, VCAM-1 and ICAM-1, are upregulated after incubation with melphalan, suggesting increase of adhesion mediated drug resistance after chemotherapy. In this context, the expression levels of important adhesion molecules on MM cells of consecutive MM patients before and after chemotherapy have been determined in this study.

Methods: The expression levels of VLA-1, VLA-4, VLA-5, LFA-1, VCAM, ICAM-1, CD138, CD38, and CD56 were determined on MM cell lines, HS-5 stromal cells, and primary myeloma cells of 20 consecutive patients by flow cytometry in comparison to isotype control. 9 patients had been pre-treated (mostly induction chemotherapy and high dose melphalan with stem cell rescue) and 11 patients had been at diagnosis without treatment. Interpatient comparison of treated and untreated patients was performed. Intrapatient analysis (before and after high dose chemotherapy) will be performed in the follow up.

Results: VLA-4 and ICAM-1 are upregulated after chemotherapy by 54% and 64%, respectively. Similar upregulation of CD38 could be observed (62%), whereas CD138 shows downregulation by about 50%. CD56, VCAM, and LFA-1 expression was not significantly altered after chemotherapy.

Conclusion: The adhesion molecules VLA-4 and ICAM-1, which are essential for MM-BMSC interaction, are upregulated after chemotherapy. This finding supports our preclinical data and the hypothesis, that adhered, primary drug resistant MM cells are selected by chemotherapy and herewith contribute to multidrug resistance in multiple myeloma.